African American have an approximately 3-5 fold increased risk of developing end stage renal disease. Recently, coding region polymorphisms (G1 and G2) in the apolipoprotein L1 (APOL1) gene has been identified that can explain this increased risk. According to recent reports, there are more than 3 million African Americans with high-risk genotype, who are at increased risk for kidney disease development. Interestingly, mutations of APOL1 can present with diverse phenotypes, including patients with hypertensive nephrosclerosis (HN) presenting with low-grade albuminuria or patients with focal segmental glomerulosclerosis (FSGS) and HIV associated renal disease (HIVAN) showing nephrotic syndrome. APOL1 is an HDL associated protein in the circulation, but glomerular and tubule epithelial cells, endothelial cells and vascular smooth muscle cells also express APOL1. APOL1 is a relatively recent gene and it is not present in rodents. Animal model studies proving that APOL1 is the causal gene for kidney disease development is lacking. The aim of the proposal is to understand APOL1-Associated Kidney Disease (AAKD) development. Aim1. A. Provide decisive evidence that APOL1 risk variants compared to the reference allele cause kidney disease B. Demonstrate that our cell type specific inducible mouse model system recapitulates human disease at a functional, histological and molecular level. C. Determine the critical cell type(s) for APOL1-mediated disease development by characterizing the phenotype of transgenic mice with podocyte, tubule epithelial cell, liver, endothelial and vascular smooth muscle specific inducible G0, G1 and G2 APOL1 expression. Aim2. Define whether lowering risk allele APOL1 levels can stabilize or reverse kidney disease Aim3. Understand the transcriptional regulation of APOL1 in podocytes Examine whether transcriptional suppression of APOL1 by STAT inhibitors can reduce APOL1 expression and ameliorate the mutant protein induced cytotoxicity. The studies shall have a broad significance, as APOL1 mutations might be the most common genetic cause of glomerulosclerosis; including FSGS.